The central problem to dermal and transdermal drug delivery is the low penetration of drugs through the outer most layer of the skin, the stratum corneum (SC). The SC is composed of dead cells (corneocytes) embedded in a lipid-rich environment. For substances such as water and drugs to penetrate into the skin they must pass through the barrier provided by the SC intercellular lipid domains. Experimental studies have shown that the lipids of the SC are organized in ordered gel or crystalline phases, unlike the typical liquid crystalline phases of most biological membranes, enabling them to function as an effective barrier. The lipid organization can be ascribed to the unique composition of the SC lipids, which is composed of mostly ceramides, free fatty acids and cholesterol. While much is known about the nature of the skin lipids, a detailed picture of the molecular organization of lipids in the stratum corneum has not been elucidated. Experimentally it is known that the SC lipids are organized in lamellar bilayer structures in which the lipid chains are highly ordered and models of the molecular arrangement have been proposed to support the experimental observations. We propose to develop both atomistically detailed and coarse-grained molecular models that will be used in future molecular modeling studies of the SC lipids to probe the compositional dependence and molecular arrangement of the lipid molecules. Atomistic models based on the CHARMM forcefield will specifically be developed for the ceramides, and will be used in conjunction with models from the literature for the free fatty acids and cholesterol. Different levels of coarse-graining, and different techniques, will be explored in the development of the coarse-grained models that will be parameterized rigorously from the atomistic simulations and validated through comparison with experimental data. This work will be unique since no prior molecular modeling studies on the lipids essential to the SC have been reported in the literature. An improved understanding of the lipid organization and interactions in the SC would greatly enhance our understanding of the skin barrier and the dermal absorption process. The work proposed will allow molecular- based insight to the compositional dependence of lipid organization and structure, which would clarify the role of abnormal lipid composition in the symptoms of diseased skin, aid development of treatments for restoring barrier function, and provide insights needed for the rational design of transdermal drug delivery systems. [unreadable] [unreadable] [unreadable]